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Analysis of BMP4 and BMP7 Signaling in Breast Cancer Cells Unveils Time

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Analysis of BMP4 and BMP7 Signaling in Breast Cancer Cells Unveils Time Rodriguez-Martinez et al. BMC Medical Genomics 2011, 4:80 http://www.biomedcentral.com/1755-8794/4/80 RESEARCHARTICLE Open Access Analysis of BMP4 and BMP7 signaling in breast cancer cells unveils time-dependent transcription patterns and highlights a common synexpression group of genes Alejandra Rodriguez-Martinez1†, Emma-Leena Alarmo1†, Lilli Saarinen2, Johanna Ketolainen1, Kari Nousiainen2, Sampsa Hautaniemi2 and Anne Kallioniemi1* Abstract Background: Bone morphogenetic proteins (BMPs) are members of the TGF-beta superfamily of growth factors. They are known for their roles in regulation of osteogenesis and developmental processes and, in recent years, evidence has accumulated of their crucial functions in tumor biology. BMP4 and BMP7, in particular, have been implicated in breast cancer. However, little is known about BMP target genes in the context of tumor. We explored the effects of BMP4 and BMP7 treatment on global gene transcription in seven breast cancer cell lines during a 6- point time series, using a whole-genome oligo microarray. Data analysis included hierarchical clustering of differentially expressed genes, gene ontology enrichment analyses and model based clustering of temporal data. Results: Both ligands had a strong effect on gene expression, although the response to BMP4 treatment was more pronounced. The cellular functions most strongly affected by BMP signaling were regulation of transcription and development. The observed transcriptional response, as well as its functional outcome, followed a temporal sequence, with regulation of gene expression and signal transduction leading to changes in metabolism and cell proliferation. Hierarchical clustering revealed distinct differences in the response of individual cell lines to BMPs, but also highlighted a synexpression group of genes for both ligands. Interestingly, the majority of the genes within these synexpression groups were shared by the two ligands, probably representing the core molecular responses common to BMP4 and BMP7 signaling pathways. Conclusions: All in all, we show that BMP signaling has a remarkable effect on gene transcription in breast cancer cells and that the functions affected follow a logical temporal pattern. Our results also uncover components of the common cellular transcriptional response to BMP4 and BMP7. Most importantly, this study provides a list of potential novel BMP target genes relevant in breast cancer. Keywords: bone morphogenetic protein, breast cancer, BMP4, BMP7, expression microarray Background regulate transcription of target genes by signaling Bone morphogenetic proteins (BMPs) are extracellular through type I and II transmembrane serine-threonine ligand molecules that belong to the transforming growth receptors. Binding of the ligand to the type II receptor factor b (TGF-b) superfamily. To date, 21 members of elicits phosphorylation of the type I receptor, which, as the human BMP family have been identified [1]. BMPs a result, is able to phosphorylate other molecules and transmit the signal. In the canonical BMP pathway, the * Correspondence: [email protected] type I receptor phosphorylates receptor-regulated † Contributed equally SMAD (homologue of Drosophila Mothers Against Dec- 1Laboratory of Cancer Genetics, Institute of Biomedical Technology, University of Tampere and Centre for Laboratory Medicine, Tampere apentaplegic) proteins (R-SMADs, SMAD-1/5/8), which University Hospital, Finland then bind to the common mediator SMAD4; the Full list of author information is available at the end of the article © 2011 Rodriguez-Martinez et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Rodriguez-Martinez et al. BMC Medical Genomics 2011, 4:80 Page 2 of 16 http://www.biomedcentral.com/1755-8794/4/80 resulting SMAD complex translocates to the nucleus to time series, using a genome-wide approach. We charac- regulate transcription of target genes [1]. The signals terized the transcriptional response of breast cancer generated by BMPs in the cell membrane may be also cells to BMP signaling in an analysis that included a transferred into the cell via ERK, JNK and p38 mitogen- temporal dimension and the comparison of different cell activated protein kinases (MAPK) [2,3]. Moreover, there lines and two BMP ligands. Finally and most impor- is crosstalk between BMP signaling and other cellular tantly, we report novel potential BMP target genes rele- signaling cascades, such as the Wnt, JAK/STAT and vant in breast cancer. Notch pathways [4-6]. BMPs were first identified as inducers of ectopic bone Methods formation in vivo [7] but were later found to be crucial Breast cancer cell lines multifunctional regulators of development [8]. During Seven breast cancer cell lines (HCC1954, MDA-MB-361, the last decade, the role of BMPs in cancer development ZR-75-30, HCC1419, SK-BR-3, MDA-MB-231 and T- has gained increasing interest [9-11]. The importance of 47D) were purchased from the American Type Culture BMP4 and BMP7 in breast cancer was highlighted in a Collection (ATCC, Manassas, VA) and cultured accord- survey of seven BMPs: these two ligands had the highest ing to the recommended conditions except for MDA- expression levels and were the most frequently MB-231 and T-47D, for which the concentration of FBS expressed among 22 cell lines and 39 primary tumor in culture media were 1% and 5%, respectively. samples [12]. The expression of BMP4 and BMP7 in breast cancer also has been demonstrated in several BMP4 and BMP7 treatments other reports [13-17]. Interestingly, BMP7 protein Recombinant human BMP4 and BMP7 proteins were expression in primary breast tumors has been associated purchased from R&D Systems (Minneapolis, MN). with accelerated bone metastasis formation and served Three cell lines (HCC1954, MDA-MB-361 and ZR-75- as an independent prognostic factor for early bone 30) were treated with both BMP4 (100 ng/ml) and metastasis in a study based on a set of 409 patient sam- BMP7 (50 ng/ml) separately. HCC1419 and SK-BR-3 ples [15] though, with a smaller set of 67 patient sam- cell lines received only BMP4 treatment (100 ng/ml), ples, this association was not established [18]. while MDA-MB-231 and T-47D were treated only with The functional significance of BMP4 and BMP7 in BMP7 (50 ng/ml). Cells were seeded on 24-well plates, breast cancer has been studied predominantly through allowed to adhere for 24 h, and treated with the BMP the use of in vitro models. BMP4 was shown to inhibit ligand or vehicle for 30 min, 1 h, 3 h, 6 h, 12 h and 24 cell proliferation in a panel of breast cancer cell lines by h (Figure 1A). Experiments were performed in triplicate inducing a G1 cell cycle arrest [14]. The effects of exo- and collected cells were pooled. genous BMP4 on breast cancer cell migration and inva- sion have also been studied. For the most part, the data Microarrays suggest promotion of these cellular abilities by BMP4 in Total RNA was extracted using the RNeasy Mini Kit several breast cancer cell lines and in normal breast (Qiagen, Valencia, CA) and the quality of RNA was vali- epithelial cells [14,19], while a study in which only dated using the Agilent RNA 6000 Nano Kit (Agilent MDA-MB-231 cells were analyzed reported the opposite Technologies, Palo Alto, CA, USA). Total RNA (500 ng) phenotype [20]. For BMP7, the results from different was used to generate fluorescent Cy-3-(vehicle treated reports and different cell lines are more variable. In cells) or Cy-5-labeled cRNA (BMP4- or BMP7-treated vitro examination of BMP7 manipulation have revealed cells) using the Agilent Low RNA Input Fluorescence cell line-specific effects on cell proliferation, migration Linear Amplification Kit (Agilent Technologies). The and invasion; BMP7 induces all of these parameters in labeled cRNAs were hybridized to the 44 K Whole MDA-MB-231 cells and inhibits cellular proliferation in Human Genome oligo microarrays (Agilent Technolo- several other cell lines [21]. In opposition, in an in vivo gies) according to the manufacturer’s protocol. Microar- xenograft mouse model of MDA-MB-231 cells, BMP7 ray slides were scanned (Agilent Microarray Scanner) reduced tumor growth as well as the formation and after hybridization, and data were extracted using the growth of bone metastases [18]. Feature Extraction software, version A.7.5.1 (Agilent In spite of the many years since the discovery of BMPs Technologies). The microarray data has been submitted and being currently a very active topic in cancer to the GEO database (accession number GSE31605). research, little is known about their target genes in tumor conditions. The present study was designed to Data analysis gainknowledgeinthistopic,byexploringtheeffectsof Themicroarraydatawerefirstsubjectedtolinearnor- BMP4 and BMP7 signaling on gene transcription in malization to allow comparison between arrays. All seven breast cancer cell lines and throughout a 6-point probes were compared to the reference sequence using Rodriguez-Martinez et al. BMC Medical Genomics 2011, 4:80 Page 3 of 16 http://www.biomedcentral.com/1755-8794/4/80 BMP4 BMP7 DEP number by cell line A Vehicle B 100ng/ml 50ng/ml 9000 8000 Treatment 7000 6000 5000 BMP4 4000 BMP7 HCC1419 MDA-MB-361 MDA-MB-231 3000 2000 Cell HCC1954 lines SK-BR-3 T-47D Number of DEPs 1000 ZR-75-30 0 9 3 1 4 1 0 1 - 3 D 5 6 3 4 R 2 7 9 3 - 1 - -4 1 - 5 -B B T B 7 C K C - C S -M C -M R H A H A Z Sample collection 30min 1h 3h 6h 12h 24h D D M M C DEP number by time point 4500 BMP4 HCC1419 4000 BMP4 HCC1954 3500 BMP4 MDA-MB-361 3000 BMP4 SK-BR-3 2500 BMP4 ZR-75-30 2000 BMP7 HCC1954 1500 BMP7 MDA-MB-231 Number of DEPs 1000 BMP7 MDA-MB-361 500 BMP7 T-47D 0 BMP7 ZR-75-30 30min 1h 3h 6h 12h 24h Figure 1 Experimental workflow and numbers of differentially expressed probes (DEPs) resulting from BMP4 or BMP7 treatment.(A) Seven breast cancer cell lines were cultured on 24-well plates, allowed to adhere for 24 h, and treated with the BMP ligand or vehicle for 30 min, 1 h, 3 h, 6 h, 12 h, and 24 h.
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